1. Field of the Invention
This invention relates to 3-(3-alkylthiopropyl)benzothiazoline derivatives which exhibit valuable pharmacological activity against convulsions induced by glutamate and are useful in the prevention and treatment of convulsive phenomena, schizophrenic disorders, and in particular the deficiency forms of schizophrenia, sleep disorders, phenomena linked to cerebral ischemia and neurological conditions in which glutamate through to be implicated, such as Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis and olivopontocerebellar atrophy. Further, the invention relates to medicaments containing said compounds or their salts with pharmaceutically acceptable acids in pure state or in the form of compositions in which they are combined with a pharmaceutically acceptable carrier. The invention also relates to a process for the preparation of said compounds and to the treatment of conditions induced by glutamate.
2. Reported Developments
Glutamate is a nonessential amino acid and the most abundant free amino acid in the central nervous system. It is the putative neurotransmitter of several clinically important pathways, including cortical association fibers, cortifugal pathways and spinal cord pathways. There is substantial evidence implicating the glutamatergic system in certain neurologic diseases associated with olivopontocerebellar atrophy, Huntington's disease, status epilepticus, hypoxia, cerebral ischemia, and hypoglycemia. Accordingly, pharmacologic manipulation of the glutamatergic system appears to have great potential for the prevention and treatment of these neurologic diseases. The prior art has found for example that: glutamate antagonists can prevent the neuronal degeneration associated with ischemia and hypoxia (Simon R. P., Swan J. H. Griffiths T., et al Blockage of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain, Science 1981; 226:850-862 and Rothman S: Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death, J. Neurosci 1984; 4:1884-1891); and glutamate receptor antagonists can be used as potent anticonvulsant agents (Schwarcz R., Meldrum B: Excitatory amino acid antagonists provide a therapeutic approach to neurological disorders, Lancet 1985; 2:140-143).
Compounds having certain structural similarity and utility to the compounds of the present invention are disclosed in U.S. Pat. No. 4,918,090.